# FREED++: Improving RL Agents for Fragment-Based Molecule Generation by Thorough Reproduction

arXiv: https://arxiv.org/abs/2401.09840 · HTML: https://mlsanity.com/paper/2401.09840/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 41 of its 100 references that are in the map.
- First posted on arXiv 18 Jan 2024.

## Builds on (most cited first, 30 of 41)

- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [Soft Actor-Critic: Off-Policy Maximum Entropy Deep Reinforcement Learning with a Stochastic Actor](https://mlsanity.com/paper/1801.01290/) (2018)
- [Playing Atari with Deep Reinforcement Learning](https://mlsanity.com/paper/1312.5602/) (2013)
- [Categorical Reparameterization with Gumbel-Softmax](https://mlsanity.com/paper/1611.01144/) (2016)
- [Soft Actor-Critic Algorithms and Applications](https://mlsanity.com/paper/1812.05905/) (2018)
- [Prioritized Experience Replay](https://mlsanity.com/paper/1511.05952/) (2015)
- [MoleculeNet: A Benchmark for Molecular Machine Learning](https://mlsanity.com/paper/1703.00564/) (2017)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Reinforcement Learning with Deep Energy-Based Policies](https://mlsanity.com/paper/1702.08165/) (2017)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [MolGAN: An implicit generative model for small molecular graphs](https://mlsanity.com/paper/1805.11973/) (2018)
- [Flow Network based Generative Models for Non-Iterative Diverse Candidate Generation](https://mlsanity.com/paper/2106.04399/) (2021)
- [Graph Convolutional Policy Network for Goal-Directed Molecular Graph Generation](https://mlsanity.com/paper/1806.02473/) (2018)
- [GuacaMol: Benchmarking Models for De Novo Molecular Design](https://mlsanity.com/paper/1811.09621/) (2018)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Molecular De Novo Design through Deep Reinforcement Learning](https://mlsanity.com/paper/1704.07555/) (2017)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Optimization of Molecules via Deep Reinforcement Learning](https://mlsanity.com/paper/1810.08678/) (2018)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction](https://mlsanity.com/paper/2303.03543/) (2023)
- [Symmetry-adapted generation of 3d point sets for the targeted discovery of molecules](https://mlsanity.com/paper/1906.00957/) (2019)
- [Deep Reinforcement Learning for De-Novo Drug Design](https://mlsanity.com/paper/1711.10907/) (2017)
- [Charformer: Fast Character Transformers via Gradient-based Subword Tokenization](https://mlsanity.com/paper/2106.12672/) (2021)
- [Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design](https://mlsanity.com/paper/2210.05274/) (2022)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [Multi-Objective GFlowNets](https://mlsanity.com/paper/2210.12765/) (2022)
- [SPICE, A Dataset of Drug-like Molecules and Peptides for Training Machine Learning Potentials](https://mlsanity.com/paper/2209.10702/) (2022)
- [Time Limits in Reinforcement Learning](https://mlsanity.com/paper/1712.00378/) (2017)
- [Hit and Lead Discovery with Explorative RL and Fragment-based Molecule Generation](https://mlsanity.com/paper/2110.01219/) (2021)

## Built on by (most cited first, 1 of 1)

- [Integrating Protein Dynamics into Structure-Based Drug Design via Full-Atom Stochastic Flows](https://mlsanity.com/paper/2503.03989/) (2025)

## Abstract (arXiv)

A rational design of new therapeutic drugs aims to find a molecular structure with desired biological functionality, e.g., an ability to activate or suppress a specific protein via binding to it. Molecular docking is a common technique for evaluating protein-molecule interactions. Recently, Reinforcement Learning (RL) has emerged as a promising approach to generating molecules with the docking score (DS) as a reward. In this work, we reproduce, scrutinize and improve the recent RL model for molecule generation called FREED (arXiv:2110.01219). Extensive evaluation of the proposed method reveals several limitations and challenges despite the outstanding results reported for three target proteins. Our contributions include fixing numerous implementation bugs and simplifying the model while increasing its quality, significantly extending experiments, and conducting an accurate comparison with current state-of-the-art methods for protein-conditioned molecule generation. We show that the resulting fixed model is capable of producing molecules with superior docking scores compared to alternative approaches.